Antidyskinetic effect of JL-18, a clozapine analog, in parkinsonian monkeys

Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapin e is related to antagonism at the dopamine D-4 receptor, we investigated th e effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzo diazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP )-treated cynomolgus monkeys with a stable parkinsonian syndrome and reprod ucible dyskinesias to L-Dopa were used in this study. They were injected su bcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus bense razide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injectio n of sterile saline was used as control. L-Dopa/benserazide increased locom otion and improved parkinsonism but also induced dyskinesias. Go-administra tion of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produ ced a dose-dependent reduction in L-Dopa-induced dyskinesias without a para llel return to parkinsonism. The present results suggest that novel selecti ve dopamine D-4 receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias. (C) 2000 Elsevier Science B.V. All rights reser ved.